HIV reservoir dynamics in the face of highly active antiretroviral therapy

AIDS Patient Care and STDs

Volumn 29, Issue 2, 2015, Pages 55-68

  Costiniuk, Cecilia T ^a   Jenabian, Mohammad Ali ^b  

^a MCGILL UNIVERSITY HEALTH CENTRE   (Canada)

^b UNIVERSITÉ DU QUÉBEC À MONTRÉAL   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; VIRUS RNA;

BLOOD; CENTRAL NERVOUS SYSTEM; FACE; GENITAL SYSTEM; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; INTESTINE LYMPHATIC TISSUE; LUNG; LYMPH NODE; REVIEW; SPLEEN; CD4+ T LYMPHOCYTE; GENETICS; HIV INFECTIONS; HUMAN IMMUNODEFICIENCY VIRUS 1; IMMUNOLOGY; ISOLATION AND PURIFICATION; PHYSIOLOGY; PROCEDURES; RECURRENT DISEASE; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; TREATMENT WITHDRAWAL; VIREMIA; VIROLOGY; VIRUS LATENCY; VIRUS LOAD; VIRUS REPLICATION;

ANTIRETROVIRAL THERAPY, HIGHLY ACTIVE; CD4-POSITIVE T-LYMPHOCYTES; HIV INFECTIONS; HIV-1; HUMANS; RECURRENCE; REVERSE TRANSCRIPTASE POLYMERASE CHAIN REACTION; RNA, VIRAL; VIRAL LOAD; VIREMIA; VIRUS LATENCY; VIRUS REPLICATION; WITHHOLDING TREATMENT;

EID: 84923148595     PISSN: 10872914     EISSN: 15577449     Source Type: Journal    
DOI: 10.1089/apc.2014.0173     Document Type: Review

References (204)

1. Chun TW, Davey RT Jr, Ostrowski M, et al. Relationship between pre-existing viral reservoirs and the re-emergence of plasma viremia after discontinuation of highly active anti-retroviral therapy. Nature Med 2000;6:757-761
2. Davey RT Jr, Bhat N, Yoder C, et al. HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci USA 1999;96: 15109-15114
3. Harrington PR, Haas DW, Ritola K, Swanstrom R. Compartmentalized human immunodeficiency virus type 1 present in cerebrospinal fluid is produced by short-lived cells. J Virol 2005;79:7959-7966
4. Bukrinsky MI, Stanwick TL, Dempsey MP, Stevenson M. Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection. Science 1991;254:423-427
5. Chun TW, Engel D, Mizell SB, Ehler LA, Fauci AS. Induction of HIV-1 replication in latently infected CD4 + T cells using a combination of cytokines. J Exp Med 1998; 188:83-91
6. Chun TW, Carruth L, Finzi D, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 1997;387:183-188
7. Moir S, Chun TW, Fauci AS. Pathogenic mechanisms of HIV disease. Ann Rev Pathol 2011;6:223-248
8. Chomont N, El-Far M, Ancuta P, et al. HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nature Med 2009;15:893-900
9. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995;373: 123-126
10. Wei X, Ghosh SK, Taylor ME, et al. Viral dynamics in human immunodeficiency virus type 1 infection. Nature 1995;373:117-122
11. Colin L, Van Lint C. Molecular control of HIV-1 postintegration latency: Implications for the development of new therapeutic strategies. Retrovirology 2009;6:111
12. McElrath MJ, Steinman RM, Cohn ZA. Latent HIV-1 infection in enriched populations of blood monocytes and T cells from seropositive patients. J Clin Invest 1991;87: 27-30
13. Crowe SM, Mills J, Elbeik T, et al. Human immunodeficiency virus-infected monocyte-derived macrophages express surface gp120 and fuse with CD4 lymphoid cells in vitro: a possible mechanism of T lymphocyte depletion in vivo. Clin Immunol Immunopathol 1992;65:143-151
14. Crowe SM, Mills J, Kirihara J, Boothman J, Marshall JA, McGrath MS. Full-length recombinant CD4 and recombinant gp120 inhibit fusion between HIV infected macrophages and uninfected CD4-expressing T-lymphoblastoid cells. AIDS Res Human Retroviruses 1990;6:1031-1037
15. Alexaki A, Liu Y, Wigdahl B. Cellular reservoirs of HIV-1 and their role in viral persistence. Curr HIV Res 2008; 6:388-400
16. Perno CF, Newcomb FM, Davis DA, et al. Relative potency of protease inhibitors in monocytes/macrophages acutely and chronically infected with human immunodeficiency virus. J Infect Dis 1998;178:413-422
17. Kim RB, Fromm MF, Wandel C, et al. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998;101:289-294
18. Mikulak J, Teichberg S, Faust T, Schmidtmayerova H, Singhal PC. HIV-1 harboring renal tubular epithelial cell interaction with T cells results in T cell trans-infection. Virology 2009;385:105-114
19. Evans VA, Lal L, Akkina R, et al. Thymic plasmacytoid dendritic cells are susceptible to productive HIV-1 infection and efficiently transfer R5 HIV-1 to thymocytes in vitro. Retrovirology 2011;8:43
20. Valentin A, Rosati M, Patenaude DJ, et al. Persistent HIV-1 infection of natural killer cells in patients receiving highly active antiretroviral therapy. Proc Natl Acad Sci USA 2002;99:7015-7020
21. Zauli G, Re MC, Davis B, et al. Impaired in vitro growth of purified (CD34 + ) hematopoietic progenitors in human immunodeficiency virus-1 seropositive thrombocytopenic individuals. Blood 1992;79:2680-2687
22. Slobod KS, Bennett TA, Freiden PJ, et al. Mobilization of CD34 + progenitor cells by granulocyte colony-stimulating factor in human immunodeficiency virus type 1-infected adults. Blood 1996;88:3329-3335
23. Neal TF, Holland HK, Baum CM, et al. CD34 + progenitor cells from asymptomatic patients are not a major reservoir for human immunodeficiency virus-1. Blood 1995;86:1749-1756
24. Manches O, Frleta D, Bhardwaj N. Dendritic cells in progression and pathology of HIV infection. Trends Immunol 2014;35:114-122
25. Emiliani S, Fischle W, Ott M, Van Lint C, Amella CA, Verdin E. Mutations in the tat gene are responsible for human immunodeficiency virus type 1 postintegration latency in the U1 cell line. J Virol 1998;72:1666-1670
26. Duverger A, Jones J, May J, et al. Determinants of the establishment of human immunodeficiency virus type 1 latency. J Virol 2009;83:3078-3093
27. Duverger A, Wolschendorf F, Zhang M, et al. An AP-1 binding site in the enhancer/core element of the HIV-1 promoter controls the ability of HIV-1 to establish latent infection. J Virol 2013;87:2264-2277
28. Lenasi T, Contreras X, Peterlin BM. Transcriptional interference antagonizes proviral gene expression to promote HIV latency. Cell Host Microbe 2008;4:123-133
29. Huang J, Wang F, Argyris E, et al. Cellular microRNAs contribute to HIV-1 latency in resting primary CD4 + T lymphocytes. Nature Med 2007;13:1241-1247
30. Blazkova J, Murray D, Justement JS, et al. Paucity of HIV DNA methylation in latently infected, resting CD4 + T cells from infected individuals receiving antiretroviral therapy. J Virol 2012;86:5390-5392
31. Kauder SE, Bosque A, Lindqvist A, Planelles V, Verdin E. Epigenetic regulation of HIV-1 latency by cytosine methylation. PLoS Pathogens 2009;5:e1000495
32. de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): Characterization of the classical HDAC family. Biochem J 2003;370:737-749
33. Ylisastigui L, Archin NM, Lehrman G, Bosch RJ, Margolis DM. Coaxing HIV-1 from resting CD4 T cells: Histone deacetylase inhibition allows latent viral expression. AIDS (London, England) 2004;18:1101-1108
34. Coull JJ, He G, Melander C, Rucker VC, Dervan PB, Margolis DM. Targeted derepression of the human immunodeficiency virus type 1 long terminal repeat by pyrrole-imidazole polyamides. J Virol 2002;76:12349-12354
35. Coull JJ, Romerio F, Sun JM, et al. The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1. J Virology 2000;74:6790-6799
36. Brooks DG, Arlen PA, Gao L, Kitchen CM, Zack JA. Identification of T cell-signaling pathways that stimulate latent HIV in primary cells. Proc Natl Acad Sci USA 2003;100:12955-12960
37. Brooks DG, Kitchen SG, Kitchen CM, Scripture-Adams DD, Zack JA. Generation of HIV latency during thymopoiesis. Nature Med 2001;7:459-464
38. Sedaghat AR, Siliciano JD, Brennan TP, Wilke CO, Siliciano RF. Limits on replenishment of the resting CD4 + T cell reservoir for HIV in patients on HAART. PLoS Pathog 2007;3:e122
39. Rouzioux C, Richman D. How to best measure HIV reservoirs?. Curr Opinion HIV AIDS 2013;8:170-175
40. Chun TW, Stuyver L, Mizell SB, et al. Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci USA 1997;94: 13193-13197
41. Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997;387:188-191
42. Zhang L, Chung C, Hu BS, et al. Genetic characterization of rebounding HIV-1 after cessation of highly active antiretroviral therapy. J Clin Investig 2000;106:839-845
43. Blankson JN, Persaud D, Siliciano RF. The challenge of viral reservoirs in HIV-1 infection. Ann Rev Med 2002; 53:557-593
44. Finzi D, Blankson J, Siliciano JD, et al. Latent infection of CD4 + T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nature Med 1999;5:512-517
45. Rong L, Perelson AS. Modeling HIV persistence, the latent reservoir, and viral blips. J Theoret Biol 2009;260: 308-331
46. Zhang Z, Schuler T, Zupancic M, et al. Sexual transmission and propagation of SIV and HIV in resting and activated CD4 + T cells. Science (New York, NY) 1999; 286:1353-1357
47. Palmer S, Maldarelli F, Wiegand A, et al. Low-level viremia persists for at least 7 years in patients on suppressive antiretroviral therapy. Proc Natl Acad Sci USA 2008;105:3879-3884
48. Siliciano RF. What do we need to do to cure HIV infection. Topics in HIV Medicine: a publication of the International AIDS Society, USA. Aug-Sep 2010;18:104-108
49. Ramratnam B, Mittler JE, Zhang L, et al. The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nature Med 2000;6:82-85
50. Maldarelli F, Palmer S, King MS, et al. ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia. PLoS Pathog 2007;3:e46
51. El-Sadr WM, Lundgren J, Neaton JD, et al. CD4 + countguided interruption of antiretroviral treatment. N Eng J Med 2006;355:2283-2296
52. Hamlyn E, Ewings FM, Porter K, et al. Plasma HIV viral rebound following protocol-indicated cessation of ART commenced in primary and chronic HIV infection. PloS One 2012;7:e43754
53. Siliciano JD, Kajdas J, Finzi D, et al. Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4 + T cells. Nature Med 2003;9:727-728
54. Chun TW, Nickle DC, Justement JS, et al. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis 2008;197:714-720
55. Gutierrez C, Diaz L, Vallejo A, et al. Intensification of antiretroviral therapy with a CCR5 antagonist in patients with chronic HIV-1 infection: Effect on T cells latently infected. PloS One 2011;6:e27864
56. Llibre JM, Buzon MJ, Massanella M, et al. Treatment intensification with raltegravir in subjects with sustained HIV-1 viraemia suppression: A randomized 48-week study. Antiviral Ther 2012;17:355-364
57. Achenbauch C, Wilkin T, et al. Impact of RAL/MVC intensification with or without HIV-rAd5 vaccination on HIV DNA: ERAMUNE-02 study. Abstract #422: Conference on Retroviruses and Opportunistic Infections, 2014
58. Saez-Cirion A, Bacchus C, Hocqueloux L, et al. Posttreatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog 2013;9:e1003211
59. Lodi S, Meyer L, Kelleher AD, et al. Immunovirologic control 24 months after interruption of antiretroviral therapy initiated close to HIV seroconversion. Arch Int Med 2012;172:1252-1255
60. Volberding P, Demeter L, Bosch RJ, et al. Antiretroviral therapy in acute and recent HIV infection: A prospective multicenter stratified trial of intentionally interrupted treatment. AIDS (London, England) 2009;23:1987-1995
61. Koegl C, Wolf E, Hanhoff N, et al. Treatment during primary HIV infection does not lower viral set point but improves CD4 lymphocytes in an observational cohort. Eur J Med Res 2009;14:277-283
62. Steingrover R, Garcia EF, van Valkengoed IG, et al. Transient lowering of the viral set point after temporary antiretroviral therapy of primary HIV type 1 infection. AIDS Res Human Retroviruses 2010;26:379-387
63. Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Eng J Med 2013;369:1828-1835
64. Ledford H. HIV rebound dashes hope of "Mississipi baby" cure. Nature News 2014. July 10; doi:10.1038/nature.2014.15535
65. Eden A, Andersson LM, Andersson O, et al. Differential effects of efavirenz, lopinavir/r, and atazanavir/r on the initial viral decay rate in treatment naive HIV-1-infected patients. AIDS Res Human Retroviruses 2010;26:533-540
66. Haubrich RH, Riddler SA, Ribaudo H, et al. Initial viral decay to assess the relative antiretroviral potency of protease inhibitor-sparing, nonnucleoside reverse transcriptase inhibitor-sparing, and nucleoside reverse transcriptase inhibitor-sparing regimens for first-line therapy of HIV infection. AIDS (London, England) 2011;25:2269-2278
67. Kuritzkes DR, Ribaudo HJ, Squires KE, et al. Plasma HIV-1 RNA dynamics in antiretroviral-naive subjects receiving either triple-nucleoside or efavirenz-containing regimens: ACTG A5166s. J Infect Dis 2007;195:1169-1176
68. Riddler SA, Haubrich R, DiRienzo AG, et al. Classsparing regimens for initial treatment of HIV-1 infection. N Eng J Med 2008;358:2095-2106
69. Molto J, Ruiz L, Valle M, et al. Increased antiretroviral potency by the addition of enfuvirtide to a four-drug regimen in antiretroviral-naive, HIV-infected patients. Antiviral Ther 2006;11:47-51
70. Murray JM, Emery S, Kelleher AD, et al. Antiretroviral therapy with the integrase inhibitor raltegravir alters decay kinetics of HIV, significantly reducing the second phase. AIDS (London, England) 2007;21:2315-2321
71. Andrade A, Rosenkranz SL, Cillo AR, et al. Three distinct phases of HIV-1 RNA decay in treatment-naive patients receiving raltegravir-based antiretroviral therapy: ACTG A5248. J Infect Dis 2013;208:884-891
72. van Leth F, Prins JM, Lange JM, Geerlings SE. Protease inhibitors and non-nucleoside reverse transcriptase inhibitors have a comparable effect on the CD4 cell change after switching to tenofovir-based regimens. AIDS (London, England) 2005;19:1722-1723
73. Wu H, Mellors J, Ruan P, McMahon D, Kelleher D, Lederman MM. Viral dynamics and their relations to baseline factors and longer term virologic responses in treatment-naive HIV-1-infected patients receiving abacavir in combination with HIV-1 protease inhibitors. J Acq Immune Defic Syndromes (1999) 2003;33:557-563
74. Sterling TR, Chaisson RE, Moore RD. HIV-1 RNA, CD4 T-lymphocytes, and clinical response to highly active antiretroviral therapy. AIDS (London, England) 2001;15: 2251-2257
75. Farzadegan H, Hoover DR, Astemborski J, et al. Sex differences in HIV-1 viral load and progression to AIDS. Lancet 1998;352:1510-1514
76. Wu H, Lathey J, Ruan P, et al. Relationship of plasma HIV-1 RNA dynamics to baseline factors and virological responses to highly active antiretroviral therapy in adolescents (aged 12-22 years) infected through high-risk behavior. J Infect Dis 2004;189:593-601
77. Nettles RE, Kieffer TL, Kwon P, et al. Intermittent HIV-1 viremia (Blips) and drug resistance in patients receiving HAART. JAMA 2005;293:817-829
78. Chen P, Hubner W, Spinelli MA, Chen BK. Predominant mode of human immunodeficiency virus transfer between T cells is mediated by sustained Env-dependent neutralization-resistant virological synapses. J Virol 2007;81: 12582-12595
79. SourisseauM, Sol-Foulon N, Porrot F, Blanchet F, Schwartz O. Inefficient human immunodeficiency virus replication in mobile lymphocytes. J Virol 2007;81:1000-1012
80. Cory TJ, Schacker TW, Stevenson M, Fletcher CV. Overcoming pharmacologic sanctuaries. Curr Opin HIV AIDS 2013;8:190-195
81. Englund G, Rorsman F, Ronnblom A, et al. Regional levels of drug transporters along the human intestinal tract: Co-expression of ABC and SLC transporters and comparison with Caco-2 cells. Eur J Pharmaceut Sci 2006; 29:269-277
82. Tucker TG, Milne AM, Fournel-Gigleux S, Fenner KS, Coughtrie MW. Absolute immunoquantification of the expression of ABC transporters P-glycoprotein, breast cancer resistance protein and multidrug resistance-associated protein 2 in human liver and duodenum. Biochem Pharmacol 2012;83:279-285
83. Paine MF, Hart HL, Ludington SS, Haining RL, Rettie AE, Zeldin DC. The human intestinal cytochrome P450 "pie". Drug Metab Disposit 2006;34:880-886
84. Zhang QY, Dunbar D, Ostrowska A, Zeisloft S, Yang J, Kaminsky LS. Characterization of human small intestinal cytochromes P-450. Drug Metab Disposit Biol Fate Chem 1999;27:804-809
85. Nicol MR, Fedoriw Y, Mathews M, et al. Expression of six drug transporters in vaginal, cervical, and colorectal tissues: Implications for drug disposition in HIV prevention. J Clin Pharmacol 2013 Dec 17, doi: 10.1002/jcph .248 [Epub ahead of print].
86. De Rosa MF, Robillard KR, Kim CJ, et al. Expression of membrane drug efflux transporters in the sigmoid colon of HIV-infected and uninfected men. J Clin Pharmacol 2013;53:934-945
87. den Haan JM, Kraal G. Innate immune functions of macrophage subpopulations in the spleen. J Innate Immun 2012;4:437-445
88. Schmidt EE, MacDonald IC, Groom AC. Comparative aspects of splenic microcirculatory pathways in mammals: The region bordering the white pulp. Scanning Microsc 1993;7:613-628
89. Llewellyn GN, Grover JR, Olety B, Ono A. HIV-1 Gag associates with specific uropod-directed microdomains in a manner dependent on its MA highly basic region. J Virol 2013;87:6441-6454
90. Schacker T, Little S, Connick E, et al. Rapid accumulation of human immunodeficiency virus (HIV) in lymphatic tissue reservoirs during acute and early HIV infection: Implications for timing of antiretroviral therapy. J Infect Dis 2000;181:354-357
91. Pantaleo G, Graziosi C, Demarest JF, et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 1993;362:355-358
92. Pantaleo G, Graziosi C, Butini L, et al. Lymphoid organs function as major reservoirs for human immunodeficiency virus. Proc Natl Acad Sci USA 1991;88:9838-9842
93. Feldmann J, Schwartz O. HIV-1 virological synapse: Live imaging of transmission. Viruses 2010;2:1666-1680
94. Rudnicka D, Feldmann J, Porrot F, et al. Simultaneous cell-to-cell transmission of human immunodeficiency virus to multiple targets through polysynapses. J Virol 2009; 83:6234-6246
95. Carr JM, Hocking H, Li P, Burrell CJ. Rapid and efficient cell-to-cell transmission of human immunodeficiency virus infection from monocyte-derived macrophages to peripheral blood lymphocytes. Virology 1999;265:319-329
96. Estes JD, Wietgrefe S, Schacker T, et al. Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor beta 1-positive regulatory T cells and begins in early infection. J Infect Dis 2007;195:551-561
97. Lafeuillade A, Poggi C, Profizi N, Tamalet C, Costes O. Human immunodeficiency virus type 1 kinetics in lymph nodes compared with plasma. J Infect Dis 1996;174:404-407
98. Lafeuillade A, Poggi C, Tamalet C, Profizi N. Human immunodeficiency virus type 1 dynamics in different lymphoid tissue compartments. J Infect Dis 1997;176: 804-806
99. Garcia F, Plana M, Arnedo M, et al. Effect of mycophenolate mofetil on immune response and plasma and lymphatic tissue viral load during and after interruption of highly active antiretroviral therapy for patients with chronic HIV infection: A randomized pilot study. J Acq Immune Defic Syndromes (1999) 2004;36:823-830
100. Brunet M, Martorell J, Oppenheimer F, et al. Pharmacokinetics and pharmacodynamics of mycophenolic acid in stable renal transplant recipients treated with low doses of mycophenolate mofetil. Transplant Intl 2000;131:S301-S305
101. Margolis DM, Kewn S, Coull JJ, et al. The addition of mycophenolate mofetil to antiretroviral therapy including abacavir is associated with depletion of intracellular deoxyguanosine triphosphate and a decrease in plasma HIV-1 RNA. J Acq Immune Defic Syndromes (1999). 2002;31:45-49
102. Margolis DM, Mukherjee AL, Fletcher CV, et al. The use of beta-D-2, 6-diaminopurine dioxolane with or without mycophenolate mofetil in drug-resistant HIV infection. AIDS (London, England). 2007;21:2025-2032
103. Jung A, Maier R, Vartanian JP, et al. Recombination: Multiply infected spleen cells in HIV patients. Nature 2002;418:144
104. Cheynier R, Henrichwark S, Hadida F, et al. HIV and T cell expansion in splenic white pulps is accompanied by infiltration of HIV-specific cytotoxic T lymphocytes. Cell 1994;78:373-387
105. Ince WL, Harrington PR, Schnell GL, et al. Major coexisting human immunodeficiency virus type 1 env gene subpopulations in the peripheral blood are produced by cells with similar turnover rates and show little evidence of genetic compartmentalization. J Virology 2009;83: 4068-4080
106. Di Mascio M, Srinivasula S, Bhattacharjee A, et al. Antiretroviral tissue kinetics: In vivo imaging using positron emission tomography. Antimicrob Agents Chemother 2009;53:4086-4095
107. Cerf-Bensussan N, Guy-Grand D. Intestinal intraepithelial lymphocytes. Gastroenterol Clin N Am 1991;20:549-576
108. Veazey RS, DeMaria M, Chalifoux LV, et al. Gastrointestinal tract as a major site of CD4 + T cell depletion and viral replication in SIV infection. Science (New York, NY) 1998;280:427-431
109. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Med 2006;12:1365-1371
110. Sandler NG, Douek DC. Microbial translocation in HIV infection: Causes, consequences and treatment opportunities. Nature Rev Microbiol 2012;10:655-666
111. De Smedt T, Pajak B, Muraille E, et al. Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo. J Exp Med 1996;184:1413-1424
112. Wang JH, Janas AM, Olson WJ, Wu L. Functionally distinct transmission of human immunodeficiency virus type 1 mediated by immature and mature dendritic cells. J Virol 2007;81:8933-8943
113. Brenchley JM, Silvestri G, Douek DC. Nonprogressive and progressive primate immunodeficiency lentivirus infections. Immunity 2010;32:737-742
114. Lederman MM, Funderburg NT, Sekaly RP, Klatt NR, Hunt PW. Residual immune dysregulation syndrome in treated HIV infection. Adv Immunol 2013;119:51-83
115. Duprez DA, Kuller LH, Tracy R, et al. Lipoprotein particle subclasses, cardiovascular disease and HIV infection. Atherosclerosis 2009;207:524-529
116. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med 2008;5:e203
117. Sandler NG, Wand H, Roque A, et al. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis 2011;203:780-790
118. Kotler DP. Intestinal disease associated with HIV infection: Characterization and response to antiretroviral therapy. Pathobiology 1998;66:183-188
119. Mehandru S, Poles MA, Tenner-Racz K, et al. Lack of mucosal immune reconstitution during prolonged treatment of acute and early HIV-1 infection. PLoS Med 2006;3:e484
120. Veazey RS, Lackner AA. Impact of antiretroviral therapy on intestinal lymphoid tissues in HIV infection. PLoS Med 2006;3:e515
121. Lerner P, Guadalupe M, Donovan R, et al. The gut mucosal viral reservoir in HIV-infected patients is not the major source of rebound plasma viremia following interruption of highly active antiretroviral therapy. J Virol 2011;85:4772-4782
122. Fijak M, Bhushan S, Meinhardt A. Immunoprivileged sites: The testis. Methods Mol Biol (Clifton, NJ). 2011; 677:459-470
123. Simpson E. A historical perspective on immunological privilege. Immunol Rev 2006;213:12-22
124. Billingham RE, Parkes AS. Studies on the survival of homografts of skin and ovarian tissue in rats. Proc Royal Soc London Series B 1955;143:550-560
125. Krohn PL. Transplantation of endocrine organs, with special reference to the ovary. Br Med Bull 1965;21:157-161
126. Shehu-Xhilaga M, Kent S, Batten J, et al. The testis and epididymis are productively infected by SIV and SHIV in juvenile macaques during the post-acute stage of infection. Retrovirology 2007;4:7
127. da Silva M, Shevchuk MM, Cronin WJ, et al. Detection of HIV-related protein in testes and prostates of patients with AIDS. Am J Clin Pathol 1990;93:196-201
128. Pudney J, Anderson D. Orchitis and human immunodeficiency virus type 1 infected cells in reproductive tissues from men with the acquired immune deficiency syndrome. Am J Pathol 1991;139:149-160
129. Nuovo GJ, Becker J, Simsir A, Margiotta M, Khalife G, Shevchuk M. HIV-1 nucleic acids localize to the spermatogonia and their progeny. A study by polymerase chain reaction in situ hybridization. Am J Pathol 1994;144: 1142-1148
130. Muciaccia B, Uccini S, Filippini A, et al. Presence and cellular distribution of HIV in the testes of seropositive subjects: An evaluation by in situ PCR hybridization. FASEB J 1998;12:151-163
131. Shevchuk MM, Nuovo GJ, Khalife G. HIV in testis: Quantitative histology and HIV localization in germ cells. J Reprod Immunol 1998;41:69-79
132. Willey S, Roulet V, Reeves JD, et al. Human Leydig cells are productively infected by some HIV-2 and SIV strains but not by HIV-1. AIDS (London, England) 2003;17:183-188
133. Philpott S, Burger H, Tsoukas C, et al. Human immunodeficiency virus type 1 genomic RNA sequences in the female genital tract and blood: Compartmentalization and intrapatient recombination. J Virol 2005;79:353-363
134. Kemal KS, Foley B, Burger H, et al. HIV-1 in genital tract and plasma of women: compartmentalization of viral sequences, coreceptor usage, and glycosylation. Proc Natl Acad Sci USA 2003;100:12972-12977
135. Tirado G, Jove G, Kumar R, et al. Differential virus evolution in blood and genital tract of HIV-infected females: Evidence for the involvement of drug and non-drug resistance-associated mutations. Virology 2004;324:577-586
136. Ghosn J, Viard JP, Katlama C, et al. Evidence of genotypic resistance diversity of archived and circulating viral strains in blood and semen of pre-treated HIV-infected men. AIDS (London, England) 2004;18:447-457
137. Zhang H, Dornadula G, Beumont M, et al. Human immunodeficiency virus type 1 in the semen of men receiving highly active antiretroviral therapy. N Eng J Med 1998;339:1803-1809
138. Craigo JK, Patterson BK, Paranjpe S, et al. Persistent HIV type 1 infection in semen and blood compartments in patients after long-term potent antiretroviral therapy. AIDS Res Human Retroviruses 2004;20:1196-1209
139. Haggerty CM, Pitt E, Siliciano RF. The latent reservoir for HIV-1 in resting CD4 + T cells and other viral reservoirs during chronic infection: Insights from treatment and treatment-interruption trials. Curr Opin HIV AIDS 2006; 1:62-68
140. Pilcher CD, Shugars DC, Fiscus SA, et al. HIV in body fluids during primary HIV infection: Implications for pathogenesis, treatment and public health. AIDS (London, England) 2001;15:837-845
141. Celum CL, Buchbinder SP, Donnell D, et al. Early human immunodeficiency virus (HIV) infection in the HIV Network for Prevention Trials Vaccine Preparedness Cohort: Risk behaviors, symptoms, and early plasma and genital tract virus load. J Infect Dis 2001;183:23-35
142. Stekler J, Sycks BJ, Holte S, et al. HIV dynamics in seminal plasma during primary HIV infection. AIDS Res Human Retroviruses 2008;24:1269-1274
143. Costiniuk CT, Kovacs C, Routy JP, et al. Short communication: Human immunodeficiency virus rebound in blood and seminal plasma following discontinuation of antiretroviral therapy. AIDS Res Human Retroviruses 2013; 29:266-269
144. Liuzzi G, D'Offizi G, Topino S, et al. Dynamics of viral load rebound in plasma and semen after stopping effective antiretroviral therapy. AIDS (London, England). 2003;17: 1089-1092
145. Cu-Uvin S, Caliendo AM. Genital tract HIV-1 RNA shedding among women with below detectable plasma viral load. AIDS (London, England) 2011;25:880-881
146. Fiore JR, Suligoi B, Saracino A, et al. Correlates of HIV-1 shedding in cervicovaginal secretions and effects of antiretroviral therapies. AIDS (London, England) 2003;17: 2169-2176
147. Neely MN, Benning L, Xu J, et al. Cervical shedding of HIV-1 RNA among women with low levels of viremia while receiving highly active antiretroviral therapy. J Acq Immune Defic Syndromes (1999) 2007;44:38-42
148. Eron JJ, Vernazza PL, Johnston DM, et al. Resistance of HIV-1 to antiretroviral agents in blood and seminal plasma: Implications for transmission. AIDS (London, England) 1998;12:F181-F189
149. Vernazza PL, Eron JJ, Cohen MS, van der Horst CM, Troiani L, Fiscus SA. Detection and biologic characterization of infectious HIV-1 in semen of seropositive men. AIDS (London, England) 1994;8:1325-1329
150. Graham SM, Jalalian-Lechak Z, Shafi J, et al. Antiretroviral treatment interruptions predict female genital shedding of genotypically resistant HIV-1 RNA. J Acq Immune Defic Syndromes (1999) 2012;60:511-518
151. McCombs J, Matsuda T, Tonnu-Mihara I, et al. The risk of long-term morbidity and mortality in patients With chronic hepatitis C: Results from an analysis of data from a Department of Veterans Affairs Clinical Registry. JAMA Intern Med 2014;174:204-212
152. Else LJ, Taylor S, Back DJ, Khoo SH. Pharmacokinetics of antiretroviral drugs in anatomical sanctuary sites: The male and female genital tract. Antiviral Ther 2011;16: 1149-1167
153. Sungkanuparph S, Overton ET, Seyfried W, Groger RK, Fraser VJ, Powderly WG. Intermittent episodes of detectable HIV viremia in patients receiving nonnucleoside reverse-transcriptase inhibitor-based or protease inhibitorbased highly active antiretroviral therapy regimens are equivalent in incidence and prognosis. Clin Infect Dis 2005;41:1326-1332
154. Leruez-Ville M, Dulioust E, Costabliola D, et al. Decrease in HIV-1 seminal shedding in men receiving highly active antiretroviral therapy: An 18 month longitudinal study (ANRS EP012). AIDS (London, England) 2002;16: 486-488
155. Wilson DP, Law MG, Grulich AE, Cooper DA, Kaldor JM. Relation between HIV viral load and infectiousness: A model-based analysis. Lancet 2008;372:314-320
156. Cohen MS, Gay C, Kashuba AD, Blower S, Paxton L. Narrative review: antiretroviral therapy to prevent the sexual transmission of HIV-1. Ann Intern Med 2007;146: 591-601
157. Wang CC, McClelland RS, Overbaugh J, et al. The effect of hormonal contraception on genital tract shedding of HIV-1. AIDS (London, England) 2004;18:205-209
158. Clemetson DB, Moss GB, Willerford DM, et al. Detection of HIV DNA in cervical and vaginal secretions. Prevalence and correlates among women in Nairobi, Kenya. JAMA 1993;269:2860-2864
159. Kovacs A, Wasserman SS, Burns D, et al. Determinants of HIV-1 shedding in the genital tract of women. Lancet 2001;358:1593-1601
160. Thiruchelvam U, Dransfield I, Saunders PT, Critchley HO. The importance of the macrophage within the human endometrium. J Leukocyte Biol 2013;93:217-225
161. Critchley HO, Kelly RW, Brenner RM, Baird DT. The endocrinology of menstruation-A role for the immune system. Clin Endocrinol 2001;55:701-710
162. Ho DD, Rota TR, Hirsch MS. Infection of monocyte/macrophages by human T lymphotropic virus type III. J Clin Invest 1986;77:1712-1715
163. Garry R, Hart R, Karthigasu KA, Burke C. Structural changes in endometrial basal glands during menstruation. BJOG 2010;117:1175-1185
164. Maybin JA, Barcroft J, Thiruchelvam U, Hirani N, Jabbour HN, Critchley HO. The presence and regulation of connective tissue growth factor in the human endometrium. Human Reprod (Oxford, England) 2012;27:1112-1121
165. Haas DW, Clough LA, Johnson BW, et al. Evidence of a source of HIV type 1 within the central nervous system by ultraintensive sampling of cerebrospinal fluid and plasma. AIDS Res Human Retroviruses 2000;16:1491-1502
166. Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nature Rev Neurosci 2006;7:41-53
167. Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev 2005; 57:173-185
168. Ransohoff RM, Kivisakk P, Kidd G. Three or more routes for leukocyte migration into the central nervous system. Nature Rev Immunol 2003;3:569-581
169. Goudsmit J, Wolters EC, Bakker M, et al. Intrathecal synthesis of antibodies to HTLV-III in patients without AIDS or AIDS related complex. Br Med J Clin Res 1986; 292:1231-1234
170. Hughes ES, Bell JE, Simmonds P. Investigation of population diversity of human immunodeficiency virus type 1 in vivo by nucleotide sequencing and length polymorphism analysis of the V1/V2 hypervariable region of env. J Gen Virol 1997;78:2871-2882
171. Williams KC, Corey S, Westmoreland SV, et al. Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: Implications for the neuropathogenesis of AIDS. J Exp Med 2001;193:905-915
172. Albright AV, Soldan SS, Gonzalez-Scarano F. Pathogenesis of human immunodeficiency virus-induced neurological disease. J Neurovirol 2003;9:222-227
173. Kolson DL, Lavi E, Gonzalez-Scarano F. The effects of human immunodeficiency virus in the central nervous system. Adv Virus Res 1998;50:1-47
174. Gartner S. HIV infection and dementia. Science (New York, NY) 2000;287:602-604
175. Erfle V, Stoeckbauer P, Kleinschmidt A, et al. Target cells for HIV in the central nervous system: Macrophages or glial cells?. Res Virol 1991;142:139-144
176. Koenig S, Gendelman HE, Orenstein JM, et al. Detection of AIDS virus in macrophages in brain tissue from AIDS patients with encephalopathy. Science (New York, NY) 1986;233:1089-1093
177. Dewhurst S, Sakai K, Bresser J, Stevenson M, Evinger-Hodges MJ, Volsky DJ. Persistent productive infection of human glial cells by human immunodeficiency virus (HIV) and by infectious molecular clones of HIV. J Virol 1987;61:3774-3782
178. Schnell G, Spudich S, Harrington P, Price RW, Swanstrom R. Compartmentalized human immunodeficiency virus type 1 originates from long-lived cells in some subjects with HIV-1-associated dementia. PLoS Pathogens 2009;5:e1000395
179. Ryzhova EV, Crino P, Shawver L, Westmoreland SV, Lackner AA, Gonzalez-Scarano F. Simian immunodeficiency virus encephalitis: Analysis of envelope sequences from individual brain multinucleated giant cells and tissue samples. Virology 2002;297:57-67
180. Kramer-Hammerle S, Rothenaigner I, Wolff H, Bell JE, Brack-Werner R. Cells of the central nervous system as targets and reservoirs of the human immunodeficiency virus. Virus Res 2005;111:194-213
181. Raivich G, Bohatschek M, Kloss CU, Werner A, Jones LL, Kreutzberg GW. Neuroglial activation repertoire in the injured brain: Graded response, molecular mechanisms and cues to physiological function. Brain Res Rev 1999;30:77-105
182. Spudich S. HIV and neurocognitive dysfunction. Curr HIV/AIDS Rep 2013;10:235-243
183. Strain MC, Letendre S, Pillai SK, et al. Genetic composition of human immunodeficiency virus type 1 in cerebrospinal fluid and blood without treatment and during failing antiretroviral therapy. J Virol 2005;79:1772-1788
184. Pillai SK, Pond SL, Liu Y, et al. Genetic attributes of cerebrospinal fluid-derived HIV-1 env. Brain J Neurol 2006;129:1872-1883
185. Kearney BP, Aweeka FT. The penetration of anti-infectives into the central nervous system. Neurol Clin 1999;17:883-900
186. Enting RH, Hoetelmans RM, Lange JM, Burger DM, Beijnen JH, Portegies P. Antiretroviral drugs and the central nervous system. AIDS (London, England). 1998; 12:1941-1955
187. Taylor S, Pereira A. Penetration of HIV-1 protease inhibitors into CSF and semen. HIV Med 2000;1:18-22
188. Wynn HE, Brundage RC, Fletcher CV. Clinical implications of CNS penetration of antiretroviral drugs. CNS Drugs 2002;16:595-609
189. Calcagno A, Cusato J, Simiele M, et al. High interpatient variability of raltegravir CSF concentrations in HIV-positive patients: A pharmacogenetic analysis. J Antimicrob Chemother 2014;69:241-245
190. Aylward EH, Henderer JD, McArthur JC, et al. Reduced basal ganglia volume in HIV-1-associated dementia: Results from quantitative neuroimaging. Neurology 1993;43: 2099-2104
191. McArthur JC, McClernon DR, Cronin MF, et al. Relationship between human immunodeficiency virus-dementia and viral load in cerebrospinal fluid and brain. Ann Neurol 1997;42:689-698
192. Barber SA, Gama L, Li M, et al. Longitudinal analysis of simian immunodeficiency virus (SIV) replication in the lungs: Compartmentalized regulation of SIV. J Infect Dis 2006;194:931-938
193. Horiike M, Iwami S, Kodama M, et al. Lymph nodes harbor viral reservoirs that cause rebound of plasma viremia in SIV-infected macaques upon cessation of combined antiretroviral therapy. Virology 2012;423: 107-118
194. Costiniuk CT, Jenabian MA. The lungs as anatomical reservoirs of HIV infection. Rev Med Virol 2014;24: 35-54
195. Agostini C, Trentin L, Zambello R, et al. Release of granulocyte-macrophage colony-stimulating factor by alveolar macrophages in the lung of HIV-1-infected patients. A mechanism accounting for macrophage and neutrophil accumulation. J Immunol (Baltimore, MD 1950) 1992;149: 3379-3385
196. Jambo KC, Banda DH, Kankwatira AM, et al. Small alveolar macrophages are infected preferentially by HIV and exhibit impaired phagocytic function. Mucosal Immunol 2014;7:1116-1126
197. Itescu S, Simonelli PF, Winchester RJ, Ginsberg HS. Human immunodeficiency virus type 1 strains in the lungs of infected individuals evolve independently from those in peripheral blood and are highly conserved in the C-terminal region of the envelope V3 loop. Proc Natl Acad Sci USA 1994;91:11378-11382
198. Singh A, Besson G, Mobasher A, Collman RG. Patterns of chemokine receptor fusion cofactor utilization by human immunodeficiency virus type 1 variants from the lungs and blood. J Virol 1999;73:6680-6690
199. Israel-Biet D, Cadranel J, Even P. Human immunodeficiency virus production by alveolar lymphocytes is increased during Pneumocystis carinii pneumonia. Am Rev Respirat Dis 1993;148:1308-1312
200. Nakata K, Rom WN, Honda Y, et al. Mycobacterium tuberculosis enhances human immunodeficiency virus-1 replication in the lung. Am J Respirat Crit Care Med 1997;155:996-1003
201. Abbud RA, Finegan CK, Guay LA, Rich EA. Enhanced production of human immunodeficiency virus type 1 by in vitro-infected alveolar macrophages from otherwise healthy cigarette smokers. J Infect Dis 1995;172:859-863
202. Baldwin GC, Buckley DM, Roth MD, Kleerup EC, Tashkin DP. Acute activation of circulating polymorphonuclear neutrophils following in vivo administration of cocaine. A potential etiology for pulmonary injury. Chest 1997;111:698-705
203. Twigg Iii HL, Weiden M, Valentine F, et al. Effect of highly active antiretroviral therapy on viral burden in the lungs of HIV-infected subjects. J Infect Dis 2008;197: 109-116
204. Twigg HL, Schnizlein-Bick CT, Weiden M, et al. Measurement of antiretroviral drugs in the lungs of HIV-infected patients. HIV Ther 2010;4:247-251